Abstract
BackgroundIndependent surveys of human gene promoter regions have demonstrated an overrepresentation of G3Xn1G3Xn2G3Xn3G3 motifs which are known to be capable of forming intrastrand quadruple helix structures. In spite of the widely recognized importance of G-quadruplex structures in gene regulation and growing interest around this unusual DNA structure, there are at present only few such structures available in the Nucleic Acid Database. In the present work we generate by molecular modeling feasible G-quadruplex structures which may be useful for interpretation of experimental data.ResultsWe have used all quadruplex DNA structures deposited in the Nucleic Acid Database in order to select a list of fragments entailing a strand of three adjacent G's paired with another strand of three adjacent G's separated by a loop of one to four residues. These fragments were further clustered and representative fragments were finally selected. Further fragments were generated by assemblying the two strands of each fragment with loops from different fragments whenever the anchor G's were superimposable. The fragments were used to assemble G quadruplex based on a superimposability criterion.ConclusionMolecular models have been generated for a large number of G3Xn1G3Xn2G3Xn3G3 sequences. For a given sequence not all topologies are possible with the available repertoire of fragments due to steric hindrance and low superimposability. Since all molecular models are generated by fragments coming from observed quadruplex structures, molecular models are in principle reliable and may be used for interpretation of experimental data. Some examples of applications are given.
Highlights
Independent surveys of human gene promoter regions have demonstrated an overrepresentation of G3Xn1G3Xn2G3Xn3G3 motifs which are known to be capable of forming intrastrand quadruple helix structures
The Protein Data Bank (PDB) [50] was searched for entries containing the words "tetraplex" or "quadruplex" and the list was filtered by visual inspection
A large number of molecular models has been generated for intrastrand G-quadruplex formed by G3Xn1G3Xn2G3Xn3G3 sequences
Summary
Independent surveys of human gene promoter regions have demonstrated an overrepresentation of G3Xn1G3Xn2G3Xn3G3 motifs which are known to be capable of forming intrastrand quadruple helix structures. As G > A point mutations abrogating the capacity of the promoter to form a quadruplex enhance transcription, while porphyrinic ligands that stabilize G4-DNA reduce transcription, it was concluded that quadruplex DNA should behave as a repressor. Such mechanism has been hypothesized for other proto-oncogenes including KRAS [11,12,13], CKIT [14], VEGF [15], CMYB [16], Rb [17] and BCL-2 [18,19]. HnRNP A1 [22], POT-1 [23] and human Werner syndrome helicase [24] have resolvase activity against this structure
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